Leishmaniasis refers to a group of diseases that afflicts 12 million persons worldwide, with an estimated 2 million new infections occurring annually (1). All three forms of the disease, visceral, cutaneous and mucosal leishmaniasis, are prevalent in our study areas in the Northeast of Brazil. The main objective of this program is to strengthen and expand knowledge of the host-parasite relationship in leishmaniasis that will allow new forms of therapy and control of leishmaniasis. The Federal University of Bahia (UFBA) Tropical Medicine Research Center was established in 1991. The Federal University of Rio Grande do Norte (UFRN) joined the TMRC in 1996 to share their expertise in leishmaniasis. Strong collaborative programs have been established between Brazilian and US investigators in tropical diseases. This proposal will emphasize the application of molecular approaches to determine host (immunologic, genetic) and parasite (genetic, phenotypic) factors contributing to the pathogenesis of tegumentary and visceral leishmaniasis. New diagnostic and therapeutic approaches are the ultimate goals of this research. An increased understanding of the pathogenesis and genetics of leishmaniasis may provide the basis for innovative clinical strategies. The program has two cores (administrative, data management) and 3 scientific projects. Project I, "The role of Leishmania braziliensis strain polymorphism on disease outcome and distribution" will determine the role of parasite polymorphisms in the different clinical forms associated to L. braziliensis infection and identify markers for the molecular diagnosis of leishmaniasis. Project II, "Protective and Pathogenic Immune Responses in Tegumentary Leishmaniasis" will identify at molecular and cellular level immunological responses associated with protection and those responses associated with pathology in individuals with subclinical L. braziliensis infection and in patients with cutaneous and mucosal leishmaniasis. The duration of immunologic memory to soluble leishmania antigens and recombinant vaccine candidates antigens will also be evaluated in individuals with a past history of L. braziliensis or L. chagasi infection. Project III, "Genetic Determinants of Leishmaniasis" will expand our knowledge of genes associated with the clinical expression of L. chagasi and L. braziliensis infection. Studies performed in theses projects will seek to identify new interventions to control and/or ameliorate leishmaniasis worldwide.